Dataset Information

Evaluating CAR-T Cell Therapy in a Hypoxic 3D Tumor Model.

ABSTRACT: Despite its revolutionary success in hematological malignancies, chimeric antigen receptor T (CAR-T) cell therapy faces disappointing clinical results in solid tumors. The poor efficacy has been partially attributed to the lack of understanding in how CAR-T cells function in a solid tumor microenvironment. Hypoxia plays a critical role in cancer progression and immune editing, which potentially results in solid tumors escaping immunosurveillance and CAR-T cell-mediated cytotoxicity. Mechanistic studies of CAR-T cell biology in a physiological environment has been limited by the complexity of tumor-immune interactions in clinical and animal models, as well as by a lack of reliable in vitro models. A microdevice platform that recapitulates a 3D tumor section with a gradient of oxygen and integrates fluidic channels surrounding the tumor for CAR-T cell delivery is engineered. The design allows for the evaluation of CAR-T cell cytotoxicity and infiltration in the heterogeneous oxygen landscape of in vivo solid tumors at a previously unachievable scale in vitro.

SUBMITTER: Ando Y

PROVIDER: S-EPMC6448565 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Evaluating CAR-T Cell Therapy in a Hypoxic 3D Tumor Model.

Ando Yuta Y Siegler Elizabeth L EL Ta Hoang P HP Cinay Gunce E GE Zhou Hao H Gorrell Kimberly A KA Au Hannah H Jarvis Bethany M BM Wang Pin P Shen Keyue K

Advanced healthcare materials 20190208 5

Despite its revolutionary success in hematological malignancies, chimeric antigen receptor T (CAR-T) cell therapy faces disappointing clinical results in solid tumors. The poor efficacy has been partially attributed to the lack of understanding in how CAR-T cells function in a solid tumor microenvironment. Hypoxia plays a critical role in cancer progression and immune editing, which potentially results in solid tumors escaping immunosurveillance and CAR-T cell-mediated cytotoxicity. Mechanistic ...[more]

PMID: 30734529

Similar Datasets

Project description:T-cells genetically engineered to express a chimeric antigen receptor (CAR) have shown remarkable results in patients with B-cell malignancies, including B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and mantle cell lymphoma, with some promising efficacy in patients with multiple myeloma. However, the efficacy of CAR T-cell therapy is still hampered by local immunosuppression and significant toxicities, notably cytokine release syndrome (CRS) and neurotoxicity. The tumor microenvironment (TME) has been identified to play a major role in preventing durable responses to immunotherapy in both solid and hematologic malignancies, with this role exaggerated in solid tumors. The TME comprises a diverse set of components, including a heterogeneous population of various cells and acellular elements that collectively contribute towards the interplay of pro-immune and immunosuppressive signaling. In particular, macrophages, myeloid-derived suppressor cells, regulatory T-cells, and cell-free factors such as cytokines are major contributors to local immunosuppression in the TME of patients treated with CAR T-cells. In order to create a more favorable niche for CAR T-cell function, armored CAR T-cells and other combinatorial approaches are being explored for potential improved outcomes compared to conventional CAR T-cell products. While these strategies may potentiate CAR T-cell function and efficacy, they may paradoxically increase the risk of adverse events due to increased pro-inflammatory signaling. Herein, we discuss the mechanisms by which the TME antagonizes CAR T-cells and how innovative immunotherapy strategies are being developed to address this roadblock. Furthermore, we offer perspective on how these novel approaches may affect the risk of adverse events, in order to identify ways to overcome these barriers and expand the clinical benefits of this treatment modality in patients with diverse cancers. Precise immunomodulation to allow for improved tumor control while simultaneously mitigating the toxicities seen with current generation CAR T-cells is integral for the future application of more effective CAR T-cells against other malignancies.

Dataset Information

Evaluating CAR-T Cell Therapy in a Hypoxic 3D Tumor Model.

Publications

Evaluating CAR-T Cell Therapy in a Hypoxic 3D Tumor Model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets